J Cancer 2020; 11(16):4771-4782. doi:10.7150/jca.44833 This issue

Research Paper

LncRNA H19-Derived miR-675-3p Promotes Epithelial-Mesenchymal Transition and Stemness in Human Pancreatic Cancer Cells by targeting the STAT3 Pathway

Feng Wang1,2#, Long Rong2#, Zhengkui Zhang1, Mingzhe Li1, Ling Ma3, Yongsu Ma1, Xuehai Xie1, Xiaodong Tian1✉, Yinmo Yang1✉

1. Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China.
2. Department of Endoscopy Center, Peking University First Hospital, Beijing 100034, People's Republic of China.
3. Department of Surgical Oncology, Peking University Ninth School of Clinical Medicine (Beijing Shijitan Hospital, Capital Medical University), Beijing 100038, People's Republic of China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wang F, Rong L, Zhang Z, Li M, Ma L, Ma Y, Xie X, Tian X, Yang Y. LncRNA H19-Derived miR-675-3p Promotes Epithelial-Mesenchymal Transition and Stemness in Human Pancreatic Cancer Cells by targeting the STAT3 Pathway. J Cancer 2020; 11(16):4771-4782. doi:10.7150/jca.44833. Available from https://www.jcancer.org/v11p4771.htm

File import instruction

Abstract

Objective: The functional role and mechanism of the long noncoding RNA (lncRNA) H19 in regulating human pancreatic cancer (PC) cell stemness and invasion have not been completely elucidated. This study aimed to evaluate the role of H19 in regulating the stemness, epithelial-mesenchymal transition (EMT), invasion and chemosensitivity of PC cells.

Methods: The sphere-forming ability was assessed using serum-free floating-culture systems. Chemosensitivity was evaluated via CCK-8 and flow cytometry assays in vitro. Migration and invasion were evaluated by transwell assays. The expression of stemness and EMT markers was detected by flow cytometry, qRT-PCR and western blot analyses. Xenograft initiation, growth and sensitivity were examined; Ki-67 nuclear staining intensity was evaluated by immunohistochemistry; and in situ apoptosis was evaluated by a TUNEL assay.

Results: H19 played an important role in maintaining PC cell stemness. Upregulated H19 expression in CAPAN-1 cells promoted tumor cell migration, invasion, EMT and chemoresistance. In contrast, downregulated H19 expression in PANC-1 cells yielded the opposite results. These effects were mediated by positively modulating the STAT3 pathway. Furthermore, SOCS5, an endogenous inhibitor of the STAT3 pathway, was a direct target of miR-675-3p, which was positively regulated by H19 in PC cells.

Conclusions: The H19/miR-675-3p signaling axis plays a critical role in maintaining the EMT process and stemness of PC cells by directly targeting SOCS5 to activate the STAT3 pathway. These data provide new insights into the oncogenic function of H19 in human PC and reveal potential targets for the development of optimal treatment approaches for this disease.

Keywords: pancreatic cancer, long noncoding RNA H19, miR-675-3p, STAT3 signaling pathway, EMT, stemness property